EP0501205B1 - Antiphlogistisches Mittel - Google Patents

Antiphlogistisches Mittel Download PDF

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Publication number
EP0501205B1
EP0501205B1 EP92102061A EP92102061A EP0501205B1 EP 0501205 B1 EP0501205 B1 EP 0501205B1 EP 92102061 A EP92102061 A EP 92102061A EP 92102061 A EP92102061 A EP 92102061A EP 0501205 B1 EP0501205 B1 EP 0501205B1
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EP
European Patent Office
Prior art keywords
galloyl
digalloyl
compounds
inflammatory
active ingredient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP92102061A
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German (de)
English (en)
French (fr)
Other versions
EP0501205A1 (de
Inventor
Hildebert Prof. Dr. Dr. Inst. für pharm. Wagner
Walter Prof. Dr. Dorsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Plantamed Arzneimittel GmbH
Original Assignee
Plantamed Arzneimittel GmbH
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Publication date
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Publication of EP0501205A1 publication Critical patent/EP0501205A1/de
Application granted granted Critical
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Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention relates to the use of certain gallic acid compounds for the production of a pharmaceutical preparation for the treatment of inflammatory diseases.
  • the pharmaceutical preparations are useful for the treatment of inflammatory diseases of all organs, in particular of rheumatic diseases, allergic and immunological diseases, asthma bronchial and other lung diseases such as obstructive bronchitis and inflammatory skin diseases (anti-inflammatory drugs).
  • inflammation is generally understood to mean a reaction of the organism and its tissues against various types of damaging stimuli. Harmful stimuli include exogenous and endogenous stimuli, such as B. To understand tissue injuries, the penetration of foreign bodies, chemical substances, bacterial toxins, allergens, immune complexes, microorganisms, pathological metabolic products as well as decay products of tumors. The classic symptoms of pain and fever are closely related to the inflammatory process.
  • mediators are closely linked to the inflammatory process. These mediators, which are of extremely great pathogenetic importance, are released from the body cells by the damaging event (noxa).
  • the most important and best-known mediators are histamine, 5-HT (5-hydroxytryptamine), bradykinin, the prostaglandins, prostacyclins, the leukotrienes, thromboxanes and the platelet activating factor PAF (platelet activating factor), which has only recently been characterized.
  • mediators which are not specified in detail, have an extremely strong effect on the contraction of the smooth muscles, lead to cardiac dysfunction and impair it Integrity of blood vessels and mucous membranes, such as B. that of the bronchial system. They also cause the aggregation of platelets and polymorphonuclear leukocytes with the serious consequences of anaphylactic narrowing of the airway, drop in blood pressure, cardiac arrhythmias, plasma exudation, tissue edema, haemoconcentration, thrombocytopenia, leukocytopenia, clumping of the platelet and lymphocytic leukocyte and polymorphic disorders.
  • the PAF factor appears to be of particular importance in the pathogenesis of inflammatory and allergic processes.
  • PAF is a glycerophosphocholine with the chemical name 1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine. This factor is affected by a number of cells, such as. B. macrophages, basophilic and neutrophilic granulocytes released when activated. The release of PAF subsequently leads to the pathological conditions described above and probably also to a number of further pathological symptoms which have not yet been fully understood. PAF does not have to act directly, but rather can develop its effects by stimulating further mediators. Recent studies have shown that PAF plays an especially important role in the genesis of clinical bronchial asthma and in other pathological conditions of the lungs, e.g. B. has obstructive bronchitis.
  • PAF can be regarded as a highly potent inflammation mediator with the pathological effects already described above.
  • a large number of the mediators mentioned above, including the PAF, are released by a membrane-bound phospholipase from phospholipids of the cell membrane, arachidonic acid on the one hand and a PAF precursor on the other.
  • the PAF precursor is converted into the active compound by an acetyltransferase.
  • non-steroidal anti-inflammatory drugs which are compounds and derivatives of salicylic acid.
  • Other compounds with a known anti-inflammatory effect are the pyrazolone derivatives, the para-aminophenol derivatives, the indole derivatives (for example indomethacin) and derivatives of propionic acid.
  • Salicylic acid or its derivatives and the other compounds of the entire class have a number of serious and very serious side effects.
  • So z. B. the prolonged administration of salicylic acid derivatives for gastric and intestinal ulceration.
  • Also known are the relative intolerance of the pyrazolone derivatives, the hepatotoxic effect of the para-aminophenol derivatives, the general intolerance of indomethacin and the ulcerative effect of the propionic acid derivatives.
  • non-steroidal anti-inflammatory drugs can possibly increase the pathological effect of the mediators by increasing the substrate for the lipoxygenase and thus for the formation of leukotrienes by the inhibition of the cyclooxygenase (substrate shift)
  • steroidal anti-inflammatory drugs Opposed to the non-steroidal anti-inflammatory drugs are the steroidal anti-inflammatory drugs, that is the corticosteroids and their derivatives.
  • the anti-inflammatory effects of corticosteroids are based on their ability to inhibit both phospholipase and lipoxygenase, thereby inhibiting the entire arachldonic acid metabolism.
  • the disadvantage of therapy with corticosteroids is the fatal side effects, of which the following should be mentioned by way of example: duodenal or ventricular ulcers, myopathy, osteoporoses, mental disorders, increased susceptibility to infection, subcapsular cataracts and the like.
  • selective lipoxygenase inhibitors such as. B. benoxaprofen
  • This class of substances also has serious side effects, such as. B. fatal exfoliative dermatitis (scalded skin syndrome).
  • gallic acid derivatives which can be isolated from the Galphimia glauca plant, either as a single compound or in any combination, have excellent anti-inflammatory effects.
  • the compounds are particularly suitable for the prophylaxis and therapy of allergic and PAF-induced bronchial asthma.
  • the invention therefore relates to the use of at least one compound selected from compounds of the general formula: R1 R2 R3 R4 1 galloyl galloyl galloyl H 2nd galloyl digalloyl galloyl H 3rd galloyl galloyl digalloyl H 4th digalloyl galloyl galloyl H 5 galloyl galloyl galloyl galloyl with Galloyl doing the rest means and digalloyl the rest means Methyl gallate and gallic acid and the pharmaceutically acceptable salts, ethers and esters either alone or in any combination for the manufacture of a pharmaceutical preparation for the treatment or prophylaxis of inflammatory diseases.
  • the general formula includes several stereoisomeric compounds which differ in the position of the groups R4O, R2O and R3O.
  • the compounds of the general formula are from Journal of Natural Products Vol. 52, No. 4, 762-768 (1989). They have an inhibitory effect on HIV reverse transcriptase and DNA polymerase in vitro.
  • the compounds methyl gallate and gallic acid are also known compounds (e.g. Merck Index, 9th Ed, 1986).
  • a particularly preferably used compound is the compound tetragalloylquinic acid, in which the radicals R1 to R4 are galloyl.
  • the above compounds can be isolated from Galphimia glauca.
  • pharmaceutical preparations also includes vegetable extracts on an aqueous or non-aqueous basis or on the basis of a pharmaceutically acceptable solvent, optionally in conjunction with other carriers, diluents and additives known in the field of pharmaceutical technology, which at least one of the above mentioned compounds alone or in any combination.
  • Such an extract contains e.g. B. in an aqueous basis essentially as active ingredients gallic acid, methyl gallate and tetragalloylquinic acid in a ratio of about 2.5: 2.5: 10.
  • the pharmaceutical preparations produced with the use according to the invention have the essential and important property of inflammatory processes of allergic pathogenesis, in particular PAF-induced effects, such as e.g. to block obstructive bronchitis, asthma bronchial, inflammatory lung diseases, angiological disorders, inflammatory vascular processes, inflammatory skin diseases etc.
  • the pharmaceutical preparations therefore have the property of steroidal anti-inflammatory drugs without, however, showing their fatal side effects and are therefore valuable overall for the prophylaxis and treatment of inflammatory processes in the broadest sense.
  • the known mediators such as B. prostaglandins, histamine, PAF, leukotrienes and thromboxanes play a role.
  • the compounds used here are also surprising in this respect because of their surprising, excellent and advantageous action consider known connections.
  • the compounds used according to the invention meet the requirement for non-steroidal anti-inflammatory drugs which inhibit the synthesis of the leukotrienes and prostaglandins and thromboxanes and counteract the effects of the PAF factor. They are free from the disadvantages associated with steroidal or non-steroidal anti-inflammatory drugs.
  • the preparations can be administered in low doses to achieve a therapeutic anti-inflammatory effect.
  • the pharmaceutical preparations can be used to treat inflammation of the joints, skin, mucous membranes and internal organs, regardless of whether the inflammation was caused by infectious agents, immunological processes or traumas. Inflammatory processes of the bronchial system, such as asthma bronchial or obstructive bronchitis, are particularly advantageous indications to be treated.
  • the medicaments can be used for the prophylaxis and treatment of vascular and heart diseases in which it appears desirable to inhibit the biosynthesis of inflammatory substances by platelets.
  • the medicaments can be used particularly advantageously for the prophylaxis or treatment of all PAF and / or leukotriene-induced phenomena and in particular for the treatment of the bronchial space.
  • the required amount of the compound to be used (hereinafter referred to as the active ingredient) in the drug for the desired therapeutic effect depends on the respective compound, the mode of administration and the subject to be treated, as well as the respective disease.
  • a suitable dose of a compound for administration to a mammal suffering from inflammation, a painful or febrile condition as previously described is about 0.1 »g to 500 mg of the active ingredient per kilogram of body weight.
  • the dose can range from 0.5 to 500 mg of the active compound per kilogram of body weight, and the most preferred dose in the range from 0.5 to 50 mg per kilogram of body weight, e.g. B. 5 to 25 mg per kilogram of body weight, which may be administered several times a day, in particular two or three times a day.
  • the appropriate dose may be significantly higher.
  • the active ingredient be administered in the form of a pharmaceutical formulation containing a compound as described above and a pharmaceutically acceptable carrier therefor.
  • the active ingredient in such a formulation is usually present in a concentration of 0.1 to 99.9% by weight of the formulation.
  • a single dose of a formulation contains between 0.1 mg and 1 g of the active ingredient.
  • the concentration of the active ingredient is preferably 1 to 2% by weight of the preparation, but the active ingredient can be up to 10% by weight.
  • Preparations intended for nasal or buccal administration such as e.g. B. self-atomizing powders, sprays or other known and conventional devices can 0.1 to 20 wt .-%, z. B. 2 wt .-% of the active ingredient.
  • the pharmaceutical preparations for use in veterinary and human medicine contain the active ingredient in conjunction with a pharmaceutically acceptable carrier and optionally other therapeutically active ingredients.
  • the carrier must be acceptable in the sense that it is compatible with the other ingredients of the formulation and has no adverse effect on the recipient of the formulation.
  • the formulations are suitably in the form of an oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) intra-articular, topical, nasal or buccal administration form.
  • the formulations are usually in the form of a single dose and can be prepared by any of the methods known in the field of pharmaceutical technology. Essentially, all of the methods include the step of bringing the active ingredient together with the carrier, optionally with one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the formulations for oral administration can be in the form of discrete units, such as. B. capsules, cachets, tablets or pastiles, each form containing a certain amount of the active ingredient. They can also be in the form of a powder or in the form of granules or in the form of a solution or a suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water emulsion or water-in-oil emulsion .
  • the active ingredient may also be in the form of a bolus, electuary or paste.
  • compositions are in the form of a tablet, this can be prepared together with one or more additional ingredients, if appropriate by compressing or pouring the active ingredient.
  • Compressed tablets can be obtained by pressing the active ingredient in a free-flowing form, e.g. B. as a powder or as granules, optionally mixed with a binder, a lubricant, an inert diluent, surface-active or dispersing agent in a suitable device.
  • Cast tablets can be made by pouring a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent in a suitable device.
  • the preparations for rectal administration may be in the form of suppositories, the active ingredient in a carrier, e.g. B. from cocoa butter is included. They can also be in the form of an enema.
  • the formulations When formulated for parenteral administration, the formulations usually contain a sterile aqueous preparation of the active ingredient, which is preferably isotonic with the blood of the recipient.
  • Preparations which are suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the active ingredient, the active ingredient optionally being in microcrystalline form, e.g. B. in the form of an aqueous microcrystalline suspension.
  • the formulations may also be in the form of a liposomal preparation or in the form of a biodegradable polymer system for the administration of the active ingredient.
  • Formulations suitable for topical administration contain liquid or semi-liquid preparations, such as. B. liniment, lotions, dressings, oil-in-water or water-in-oil emulsions, such as. B. creams, ointments or pastes, or solutions or suspensions, such as. B. drops.
  • the active ingredient for ophthalmic administration can be in the form of aqueous eye drops, for example in the form of a 0.1 to 1.0% solution.
  • Formulations suitable for administration through the nose or into the oral cavity are in the form of a self-atomizing powder or in the form of spray preparations, e.g. B. as an aerosol. After dispersion, the formulations preferably give a particle size in the range from 1 to 200 ⁇ m.
  • Formulations can also contain the active ingredient in an aqueous or dilute alcoholic solution. If necessary, the active ingredient can be sprayed into a fine mist that is inhaled by the patient.
  • Such pharmaceutical preparations usually contain a flavor, such as. B. sodium saccharin and an essential oil.
  • a buffer substance and / or a surface-active agent can also be used in such preparations together with preservatives, such as. As methyl hydroxybenzoate may be included.
  • preparations suitable for administration through the nose consist of a coarse powder, which has a particle size of 20 to 500 »m, which is administered in the same way as snuff.
  • the formulations can contain one or more other customary and known components, such as. B. diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives, antioxidants, emulsifiers and the like.
  • Galphimia glauca (Thyrallis glauca) is a plant from the Malpighiacaen family native to Central America.
  • the dried plant is used, which is first extracted exhaustively with alkanols having 1 to 3 carbon atoms, such as methanol, ethanol and / or propanol, in particular with methanol, using known methods. This can be done by Soxhlet extraction, percolation, or maceration. Supercritical gases (e.g. CO2 or butane) can also be used for extraction processes known per se (fraction I).
  • the more lipophilic portions are separated from the extract by taking up the extract with water and extracting the mixture with chlorinated hydrocarbons with a boiling point of at most 120 ° C., in particular with chloroform and / or methylene chloride (Fraction III).
  • the remaining aqueous phase is mixed with esters of acetic acid with alkanols with 1 to 4 carbon atoms, e.g. B. methyl, ethyl, propyl and / or butyl acetate, especially extracted with ethyl acetate; an intermediate polar fraction passes into the ethyl acetate phase and is isolated (fraction II).
  • the more hydrophilic constituents are separated off from this fraction, in particular by means of flash chromatography with silica gel as the stationary phase with methylene chloride / acetone / methanol / formic acid as the eluent; a typical eluent contains 90% methylene chloride, 10% acetone and 10% methanol, to which 1% formic acid is added.
  • the fraction that passes first is further processed if necessary (extract); the subsequent, more hydrophilic fraction contains only flavone glycosides and is pharmacologically ineffective.
  • the lipophilic fraction obtained in the chromatography described above contains predominantly gallic acid, methyl gallate, quercetin and some by-products according to the thin layer chromatogram.
  • To separate the formic acid contained in it about 20 ml of distilled water is added to the fraction and the organic solvent is carefully removed on the rotary evaporator.
  • the aqueous formic acid solution was then placed on a column packed with RP material and equilibrated with water. The formic acid was eluted by water and the active substances sought stuck to the beginning of the column; they were eluted from the column with 70% methanol and the remaining methanol was evaporated. The remaining aqueous solutions were lyophilized.
  • fraction II is first hydrolyzed by adding HCl (16% HCl; 15 min., 60 ° C.). The mixture is then isolated on a silica gel column using an ethyl acetate / methanol / water / formic acid solvent system (85: 10: 3: 0.5) and by preparative HPLC on RP material using acetonitrile / water as the solvent system. The isolated compound was identified and characterized as tetragalloylquinic acid by 1 H-NMR and 13 C-NMR analyzes.
  • Groups of 10 to 14 animals were divided into two subgroups and either with the material to be examined or with Control solutions treated. After a week, the animals were treated a second time, with those treated with the control receiving the active compound and vice versa (each animal received the plant extract, the fraction or compound to be tested or the appropriate solvent once).
  • Ovalbumin, histamine hydrochloride and acetylcholine were dissolved in physiological saline (1:99, 1: 999, 1: 99 w / v), PAF first in ethanol and then in saline containing 0.25% BSA to a final concentration of 1 »g PAF / ml dissolved.
  • Ovalbumin, PAF, histamine and acetylcholine were administered as an aerosol that was ultrasonically nebulized.
  • the individual compounds methyl gallate, gallic acid and quercetin show approximately the same activity in preventing bronchial obstruction after allergen inhalation and in the case of PAF-induced bronchial obstruction, the methyl gallate shows somewhat higher activity than the mixture of quercetin, gallic acid and protocatechic acid.
  • the compound tetragalloylquinic acid showed the highest activity, which at the low oral dose of 5 mg / kg inhibited the bronchial reactions to an allergen stimulus by 86 ⁇ 24% and a bronchial reaction induced by PAF by about 60%.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP92102061A 1991-02-26 1992-02-07 Antiphlogistisches Mittel Expired - Lifetime EP0501205B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4106026A DE4106026A1 (de) 1991-02-26 1991-02-26 Pharmazeutische zubereitungen enthaltend eine gallussaeureverbindung und/oder quercetin sowie verfahren zur isolierung dieser verbindungen
DE4106026 1991-02-26

Publications (2)

Publication Number Publication Date
EP0501205A1 EP0501205A1 (de) 1992-09-02
EP0501205B1 true EP0501205B1 (de) 1995-05-24

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ID=6425927

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Application Number Title Priority Date Filing Date
EP92102061A Expired - Lifetime EP0501205B1 (de) 1991-02-26 1992-02-07 Antiphlogistisches Mittel

Country Status (5)

Country Link
US (1) US5260335A (fi)
EP (1) EP0501205B1 (fi)
JP (1) JP3114895B2 (fi)
AT (1) ATE122882T1 (fi)
DE (2) DE4106026A1 (fi)

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US6130503A (en) * 1997-03-04 2000-10-10 Pioneer Electronic Corporation Electron emission device and display using the same
US20080153761A1 (en) * 1998-04-08 2008-06-26 Theoharides Theoharis C Compositions for protection against superficial vasodilator flush syndrome, and methods of use
US7906153B2 (en) * 1998-04-08 2011-03-15 Theta Biomedical Consulting & Development Co., Inc. Anti-inflammatory compositions for treating multiple sclerosis
US20050220909A1 (en) * 2004-03-30 2005-10-06 Theoharides Theoharis C Composition for protection against superficial vasodilator flush syndrome
US6689748B1 (en) * 1998-04-08 2004-02-10 Theoharis C. Theoharides Method of treating mast cell activation-induced diseases with a proteoglycan
US6984667B2 (en) * 1998-04-08 2006-01-10 Theta Biomedical Consulting And Development Co. Synergistic proteoglycan compositions for inflammatory conditions
US7799766B2 (en) * 1998-04-08 2010-09-21 Theta Biomedical Consulting & Development Co., Inc. Composition for treating hormonally-dependent cancers
US6020069A (en) * 1998-06-18 2000-02-01 E. I. Du Pont De Nemours And Company Cathodic electrocoating composition containing an epoxy resin chain extended with a primary amine
US20040230559A1 (en) * 1999-08-09 2004-11-18 Mark Newman Information processing device and information processing method
US7029656B2 (en) * 1999-12-23 2006-04-18 Coifman Robert E Methods and formulations for the efficient delivery of water-insoluble drugs by nebulizer
US20060171897A1 (en) * 1999-12-23 2006-08-03 Coifman Robert E Methods and formulations for the efficient delivery of drugs by nebulizer
KR100470158B1 (ko) * 2001-12-05 2005-03-08 주식회사한국파마 기린초 추출물, 이로부터 분리한 화합물 및 이들을유효성분으로 함유하는 항염증용 약제학적 조성물
US7101577B2 (en) 2003-08-25 2006-09-05 National Yang-Ming University Extract of plant Dendrobii caulis and preparing process thereof
US7923043B2 (en) * 2004-03-30 2011-04-12 Theta Biomedical Consulting & Development Co., Inc. Method for protecting humans against superficial vasodilator flush syndrome
WO2008080162A2 (en) * 2006-12-22 2008-07-03 The Johns Hopkins University Anti-cholesterolemic compounds and methods of use
US9176146B2 (en) * 2009-08-03 2015-11-03 Theta Biomedical Consulting & Development Co., Inc. Methods of treating autism spectrum disorders and compositions for same
US9050275B2 (en) * 2009-08-03 2015-06-09 Theta Biomedical Consulting & Development Co., Inc. Methods of screening for and treating autism spectrum disorders and compositions for same
KR101357675B1 (ko) 2012-03-22 2014-02-05 경희대학교 산학협력단 오배자 추출물을 유효성분으로 함유하는 만성폐쇄성 폐질환 예방 및 치료용 약학적 조성물
JP2014114283A (ja) * 2012-11-19 2014-06-26 Fujifilm Corp ポリフェノールの製造方法
US9034401B1 (en) 2014-01-23 2015-05-19 Matrixx Initiatives, Inc. Pharmaceutical compositions comprising plant extracts and methods for reducing duration of a common cold using same
AU2019241169A1 (en) * 2018-03-26 2020-10-08 Wise Ally Holdings Ltd Method of delivering amphiphilic bioactive substances targeting the respiratory tract

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US4755504A (en) * 1985-10-03 1988-07-05 Yaguang Liu Pharmaceutical composition from Tienchi
CA2001898A1 (en) * 1988-10-31 1990-04-30 Kuo-Hsiung Lee Inhibition of human retroviruses

Also Published As

Publication number Publication date
EP0501205A1 (de) 1992-09-02
JPH05213744A (ja) 1993-08-24
JP3114895B2 (ja) 2000-12-04
DE4106026C2 (fi) 1993-08-26
ATE122882T1 (de) 1995-06-15
DE59202280D1 (de) 1995-06-29
DE4106026A1 (de) 1992-08-27
US5260335A (en) 1993-11-09

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